Several different methods of synthesis of 5-chloro-4-(2-imidazolin-2-yl-amin)-2,1,3-benzothiadiazole, or tizanidine, have been described.
According to the original U.S. Pat. No. 3,843,668 tizanidine is prepared with the use of compounds of general formula IIa,
where X represent a reactive removable group —NHNO2, —S—R1, —O—R1 or —NHR1, where R1 means a hydrogen atom or an alkyl with 1 to 3 carbon atoms. This reactive group is substituted by a reaction with ethylene diamine and at the same time cyclization occurs, producing tizanidine.
According to the Swiss method CH 579,565 tizanidine is prepared by cyclization of compounds of general formula IIb,
where Y represents an oxygen or sulphur atom, in an inert solvent in the presence of bases (e.g. alkali metal and alkaline earth hydroxides) and of certain compounds of the heavy metals mercury and lead.
According to other methods tizanidine is prepared by means of a reaction of 2-amino-4-chloro-2,1,3-benzothiadiazole of formula (IIc)
with the imidazolidine derivative of formula IId (Z═O) as described in patent no. EP 644 192, or with the derivative IId (Z═S) as specified in the patent no. CZ 286 717, where R represents a hydrogen atom, a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl or alkoxy group.
In these patents dehydrocondensation agents are used for the reaction, such as phosphorus(V) oxychloride, or sulfuric acid, phosphoric acid, sulfuryl chloride, or dicyclohexylcarbodiimide.
A common characteristic of the above mentioned methods of synthesis is that the last steps involve several reactions carried out by mean of reactive agents, which results in contamination of thus prepared tizanidine by a number of chemical impurities, as well as of coloured contaminants that are difficult to remove.
These coloured contaminants, although they are usually present in undetectable quantities, can make the final product, tizanidine hydrochloride in this case, unsatisfactory as regards its appearance or colour of its solution.
Preparation of tizanidine hydrochloride is described in German patent no. DE 3 610 407. The tizanidine base of formula I is dissolved in DMF, filtered with active coal and the filtrate is saturated with gaseous hydrogen chloride at ca. 60° C., producing crude tizanidine hydrochloride. The latter is aspirated and dissolved in a water/ethanol mixture and, after cooling down, tizanidine hydrochloride crystallizes.
According to Russian patent no. RU 2 234 506 concentrated hydrochloric acid is added to a suspension of the tizanidine base in ethanol, the whole is dissolved when hot and, after filtering and cooling down, tizanidine hydrochloride crystallizes.
PCT patent application no. WO 2008/008394 describes the preparation of various forms of tizanidine succinate by mixing of the tizanidine base with succinic acid or by mixing of tizanidine hydrochloride with the sodium salt of succinic acid.
Disadvantages of the Above Mentioned Methods:                pure tizanidine base is often used as the starting material, which must be first prepared, most frequently by crystallization;        Obtaining the pure base is demanding for time and energy. During crystallization its losses occur, during dissolving or concentration of solutions it is subject to thermal exposure, which produces impurities;        Another common disadvantage is a relatively low solubility of tizanidine base and tizanidine hydrochloride in commonly used solvents that are described in the above-mentioned patents.        
The authors of the present invention have found out that for crystallization of the tizanidine base in methanol, as described e.g. in U.S. Pat. No. 3,843,668, at least 37 ml of methanol must be used for dissolution of 1 g of the tizanidine base.
Similarly, to achieve crystallization of tizanidine hydrochloride, as described e.g. in patent no. EP 644 192, at least 43 ml of ethanol must be used for dissolution of 1 g of tizanidine hydrochloride.
In order to eliminate the above mentioned disadvantages the authors of the present invention have performed extensive research with the following results. During the preparation of tizanidine hydrochloride a number of hitherto unknown dependencies have been discovered.